Ovarian cancer kills more women than all the other gynecologic cancers combined and is the fourth leading cause of cancer death among women in the United States. In fact, one in 57 women will be ultimately diagnosed with ovarian cancer. When this cancer is detected early, the five-year survival rate is greater than 90%. However, only 24% of the cancers are detected early. As a result most ovarian cancers are detected in more advanced stages in which the cancer cells have spread outside the ovary. Once the ovarian cancer has spread, the five-year survival rate decreases to less than 25%.
Treatment of patients with ovarian cancer consists of surgery to remove the ovary, the uterus and the tumor. This is usually followed by platinum-based (carboplatin and cisplatin) chemotherapy. In spite of these intense surgical and chemotherapeutic treatments, the ovarian cancer more often than not recurs. At this point the patients are given salvage chemotherapy and possibly de-bulking surgery to remove the tumors that are usually distributed throughout the peritoneum. Again platinum-based chemotherapy is often used to treat the recurrent ovarian cancers but many of the ovarian cancer cells are resistant to these platinum-based agents, and thus these drugs are relatively ineffective. Increasing the dosage of platinum-based drugs is not an effective approach because these drugs are very toxic.
The overall effectiveness of any regimen for advanced ovarian cancer containing a non-platinum based drug has not yet been established. The inability of the initial chemotherapy to effectively destroy the ovarian cancer results in its recurrence and ultimately the loss of life. Progesterone (also known as 4-Pregnene-3,20-dione or P4) is a steroid hormone secreted by the ovary. Progesterone influences the function of numerous mammalian organ systems including regulation of the function of the hypothalamus, pituitary, ovary, uterus and mammary gland.
Progesterone also affects the various pathological states of these tissues including endometriosis and cancers of the ovary and breast. Depending on the ovarian cell type, progesterone can be either apoptotic (inducing cell death and thereby inhibiting cell growth) or anti-apoptotic (promoting cell growth). It has been observed that progesterone protects against ovarian cancer.
Progesterone regulates the function of the normal and neoplastic mammalian ovary through genomic (or nuclear) and non-genomic (or membrane-initiated) mechanisms. In the genomic mechanism, progesterone binds and activates progesterone receptors (PGR), namely progesterone receptors A and B (PGR-A and PGR-B), which translocate to the nucleus of the cell where they function as transcription factors, inducing the expression of numerous specific genes. In the non-genomic mechanism, progesterone also evokes rapid responses by binding to membrane receptors, including Progesterone Receptor Membrane Component-1 (PGRMC1), which was initially identified as a membrane progesterone binding protein in liver. PGRMC1 forms a progesterone receptor complex with Plasminogen Activator Inhibitor mRNA Binding Protein-1 (PAIRBP1).
The genomic mechanism of progesterone is independent from its non-genomic mechanism. It is generally believed that the protective action of progesterone against ovarian cancer is achieved through PGR in the genomic mechanism. However, it has also been recognized that PGR is expressed within the ovary in a cell specific and hormonally regulated manner. One of the major pharmaceutical agents developed on the basis of PGR's genomic actions is RU486. However, the effectiveness of this pharmaceutical agent in the treatment of ovarian cancer is questionable.
Therefore, there is a great need for pharmaceutical compositions and methods to improve the effectiveness of chemotherapy to treat ovarian cancer by regulating the action of progesterone.